KOA is a musculoskeletal disease characterized by progressive cartilage loss, usually presenting by chronic pain, limitation of movement, and disability (22). In the current work, the median WOMAC score was 48 with IQR: 39–63, so severe knee affection was remarkable among most of OA patients as the total WOMAC score (a disease-specific grading scale) is 96. As expected, this patients’ WOMAC score was significantly higher compared to controls (with median 9 and IQR: 3–21), P < 0.0001. Furthermore, the three subscales of WOMAC index score; pain, stiffness, and physical activities showed significantly higher values among KOA patients compared to controls. Similar results were reported by other studies (19, 23–25).
In agreement with previous studies (26–29), this current work found that older age ≥ 45 years was associated with higher risk of KOA (OR = 13.0, 95% CI: 2.7–62.9). This could be interpreted by the degenerative changes occur in the cartilage, the osteophytes development, and the decreased muscle mass that occur with old age resulting in joint destruction. Moreover, increased matrix MMP production and proinflammatory cytokines associated with the aging process decrease matrix synthesis, increase susceptibility to cell death and trigger joint degradation. These conditions may be end by joint cartilage damage (29).
The current study revealed that females were at higher risk of the KOA with OR = 1.8 (95%CI: 1.1-3.0), P < 0.05 and this result was in adherence to prior studies (30–31). Furthermore, the loss of the protective effect of estrogen hormone on articular cartilage could be the cause of rapid progression of KOA among post-menopausal women. These annotations, together with anatomical variations between men and women, that represented by thinner cartilage and greater valgus knee angle, may explain the higher rate of articular cartilage loss and the greater KOA severity in women (32–33). Moreover, estrogen contributes in nerve growth factor (NGF) regulation by decreasing NGF expression in chondrocytes, which is essential for the development of OA pain. Accordingly, estrogen plays a role in decreasing OA pain, which explain the postmenopausal severity of KOA symptoms. On the other hand, androgens are the precursors for estrogen. Similar to estrogen, androgens take part in cartilage protection. Androgen levels are high in men and low in women, this could explain why men have lower risk of OA (34).
Our findings show evidence that obesity was one of the risk factors for KOA as demarcated by high BMI ≥ 35 that significantly increased the risk of the disease with AOR = 5.3 (95%CI: 1.8–15.7). This was in accordance with previous studies stating that obesity was one of the major risk factors for KOA (35–39), and that every 5-unit rise in BMI results in increasing the risk of KOA by 35% (40). In addition, Visser et al (41) had found an association between high mass/skeletal muscle ratio and KOA. Moreover, in agreement with our study, Szilagyi et al (42) stated that obesity and female gender represent vital risk factors for KOA. This association can be attributed to the metabolic, biological, and immunological sequels of the obesity (36). In addition, the greater body weight increases the mechanical weight-bearing pressure on the knee joint and increases the tumor necrosing factor α (TNFα) and interleukin-1β (IL-1β) levels that activate the ruin of the ECM cartilage, thereby increasing the probability of KOA. Furthermore, the low-grade systemic inflammation caused by some molecules such as interleukin-6 (IL-6), IL-1β, TNFα, leptin, and adiponectin may play a role in obesity association with KOA (40, 43–44).
Hypertension and kidney disease significantly increased the risk of KOA by around two times as shown by our study, OR (95%CI) were 2.0 (1.2–3.4) and 2.4 (1.3–4.5) respectively, P < 0.05. These findings were consistent with a study done by Ren et al (28). Additionally, the pooled results of two meta-analyses performed by Zhang et al and Lo et al (45–46) showed that hypertension was significantly associated with increase the occurrence of KOA. Moreover, according to the results of a study done on Korean population, there was a significantly higher prevalence of KOA among hypertensive patients (47). In addition, Puenpatom and Victor (48) detected higher prevalence of hypertension among US patients with OA than in those without OA. Hypertension could be an isolated risk factor for KOA. However, because hypertension has been known to be associated with many overlapping factors, it is still debatable that KOA is associated with hypertension. Common risk factors, such as obesity, aging, and chronic inflammation have been involved in the probable mechanisms of the relation between hypertension and KOA, in addition to the vital role played by the proinflammatory cytokine interleukin-6 in both diseases (49). Regarding the reason behind kidney disease association with KOA, it could be the medication used especially nonsteroidal anti-inflammatory drug (NSAID) treatment to alleviate the associated pain in addition to the presence of chronic inflammation in both diseases (28).
In our study, we reported prolonged standing and severe physical activity as important predictive values for KOA, OR (95%CI): 4.0 (1.5–10.9) and 2.6 (1.1–6.4) respectively, P < 0.05. These findings are highly consistent with previous systematic reviews which stated that physically demanding occupations that requires prolonged standing as well as strenuous efforts were all associated with a higher risk of KOA (50). Lementowski and Zelicof (36) stated that severe mechanical forces exerted on the joints are a considerable cause of OA.
Besides the above investigated risk factors, we examined the ADAMTS14 rs4747096 genotype among KOA patients and controls and it was found a statistically significant difference between the two groups. The frequency of ADAMTS14 gene rs4747096 genotypes among patients with KOA was for AA 73.5%, AG 25.7% and GG 0.7% compared to controls 963%, 31.3% and 5.6% respectively and the frequency of alleles among patients was for A 86.4% and G 78.7% compared to controls (78.7% and 21.3% respectively, P < 0.05. This was in line with the findings of a meta-analysis performed by Li et al (51). Most previous studies of different populations have found a significant association between the ADAMTS14 rs4747096 genotype and the susceptibility to OA regarding the genotype distribution (13, 52–55) and the allele frequency (52, 54) indicating this genotype as a high-risk factor for OA. In agreement with our results, Mostafa et al (54) investigated the ADAMTS14 rs4747096 genotype among Egyptian population (42 KOA and 31 controls without OA) and showed that AA genotype frequency was significantly higher among patients compared to the control group and the A allele was significantly more frequent among KOA patients. In accordance, a Turkish study conducted by Haberal et al (56) on 300 KOA patients, AA were the most common genotype. Furthermore, in a study conducted by Poonpet et al (52) among 108 Thai patients with severe KOA and 119 controls without OA, there was a significant association between the AA genotype and KOA and between A allele and KOA among female patients. However, they did not find any association between the rs4747096 polymorphism and KOA among males.
In contrast to our results, Ma et al (13) examined the ADAMTS14 rs4747096 genotype among 346 Chinese Han KOA patients and 480 controls found that the G allele was significantly higher among KOA patients than in the control group and observed significant differences in the genotype frequency. Also, they showed that the GG genotype and the GG/AG combination were more frequent among patients than in controls without OA. Furthermore, Rodriguez-Lopez et al (53) found that the GG genotype was significantly associated with KOA among European Caucasians patients and the difference was clear between patients and controls with predominance in women. Additionally, in the women patients, they observed some indication that G allele has dominant effect.
Our analysis of the inheritance model among the studied group demonstrated an inheritance of ADAMTS14 rs4747096 polymorphism with an autosomal dominance aspect model, since the AA and AG genotypes significantly increased the risk of KOA, OR = 7.9 (95%CI: 0.97-70.0), P < 0.05 compared to recessive model, OR = 1.6 (95%CI: 0.95–2.8), P > 0.05. In consistent with our findings, Poonpet et al (52) found association of ADAMTS14 rs4747096 polymorphism with female KOA patients and showed that the inheritance model of ADAMTS14 rs4747096 gene polymorphism was of an autosomal dominance aspect and the AA and AG genotypes significantly increased risk of the disease. These results differ from the inheritance model findings of Ma et al (13) who concluded that the GG genotype and the GG/AG combination were more common among KOA patients than controls and elevated the risk of KOA in the dominant model. Additionally, Rodriguez-Lopez and colleagues (53) indicated a dominant aspect of the G allele in the women KOA patients. Meanwhile, another Turkish study noticed that there was no statistically significant relationship between severe KOA and the ADAMTS14 rs4747096 polymorphisms among 300 KOA patients (56). Our findings also showed that there was no significant association between the severity of KOA (median level of total WOMAC score) and different ADAMTS14 gene rs4747096 genotypes among patients with KOA.
The contradictory results about the relation between KOA and ADAMTS14 gene rs4747096 SNP in different studies may be due to different genetic distributions between different ethnic populations and different polymorphisms of the same gene affecting the development of KOA. In addition, these conflicting results could be attributed to the sample size, age and sex of the participants, and the severity of the disease. Moreover, geographical factors and environmental conditions such as lifestyle, physical activity, and diet can cause variations in gene-to-gene interactions (56).
There are some limitations in the current study. The study only assessed the association between KOA and SNPs of ADAMTS14 gene rs4747096, but not other gene types and this could lead to unsuitable decision about the genetic effect on KOA risk. The results cannot be representative or generalized because of the small sample size and the sample was taken from a single center.